Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3.[C-:19]#[N:20].[K+].O>CN(C)C=O>[C:19]([CH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3)#[N:20]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCCl)C2
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCC#N)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
2-(2-Chloroethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.5 g) was dissolved in dimethylformamide (50 ml). To the solution, potassium cyanide (2.0 g) was added and stirred at 100° C. for three hours. After the reaction was completed, the reaction liquid was condensed under reduced pressure. Water was added thereto and extraction was performed with chloroform. The chloroform phase was dried and condensed under reduced pressure. The residue was recrystallized from a solvent mixture of chloroform-ether to obtain 1.4 g of 2-(2-cyanoethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as pale yellow prisms (96.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=2)[CH3:20])[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: CC(Br)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1C(C)c1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 1-(1-bromoethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 424.23 g/mol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:13])[CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C)C=O>[CH3:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([CH2:2][N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)[CH:12]=[CH:11]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccc2cc(CCl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2cc(CN3CCN(c4ccccn4)CC3)ccc2c1

Procedure:
A mixture of 11.0 g. of 2-chloromethyl-6-methylnaphthalene, 7.0 g. of sodium carbonate and 10.0 g. of 2-pyridylpiperazine in 75 ml. of dimethylformamide is stirred for six hours. The reaction mixture is cooled, filtered and the filtrate is concentrated. The precipitate is then washed with water and crystallized from ethanol to yield 1-(6-methyl-β-naphthylmethyl)-4-(2-pyridyl)piperazine.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[C:3]#N.[H-].C([Al+]CC(C)C)C(C)C.[OH2:22].Cl>CCCCCC>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:22]
Reactant: CC(C)(C#N)c1ccccc1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To a solution of 2-methyl-2-phenylpropanenitrile (290 g, 2.00 mol) in hexane (2000 mL) at 0° C. under N2 is added diisobutylaluminum hydride (DIBAL-H) (2600 mL, 1M in hexane) over a period of 80 minutes. The reaction mixture is stirred at 6-14° C. for 15 minutes, then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture is cooled to 0° C. and H2O (50 mL) is added slowly during 1 hour. Aqueous HCl (900 mL, 15%) is then added slowly to maintain a gentle reflux. The reaction mixture is stirred for 17 hours and the organic phase is separated. The aqueous layer is extracted with ethyl acetate (400 mL) and the combined organic layers are washed with water (300 mL), brine (300 mL) and dried over Na2SO4. The organic extracts are filtered and concentrated to give 2-methyl-2-phenylpropanal as an oil (275 g, 92.8% yield, 98.2% by HPLC area).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Br:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([Br:30])[C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)C(Br)c1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reaction time: 8 h
Yield: 16.9 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-bromosuccinimide (0.024 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.010 g, 17%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7]Cl)[CH2:4][CH3:5])[CH3:2].CN(CCCCl)C.[CH3:16][C:17]1[CH:35]=[C:20]2[NH:21][C:22](=[O:34])[C:23]3[CH:28]=[N:27][C:26]4[N:29]([CH3:33])[N:30]=[C:31]([CH3:32])[C:25]=4[C:24]=3[N:19]2[N:18]=1>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:21]1[C:22](=[O:34])[C:23]2[CH:28]=[N:27][C:26]3[N:29]([CH3:33])[N:30]=[C:31]([CH3:32])[C:25]=3[C:24]=2[N:19]2[N:18]=[C:17]([CH3:16])[CH:35]=[C:20]12)[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: Cc1cc2[nH]c(=O)c3cnc4c(c(C)nn4C)c3n2n1
Agent: CN(C)CCCCl
Product: CCN(CC)CCn1c(=O)c2cnc3c(c(C)nn3C)c2n2nc(C)cc12

Procedure:
By substituting diethylaminoethyl chloride for the dimethylaminopropyl chloride and utilizing the 2,8,10-trimethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one product of Example 12 instead of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one in the procedure of Example 4, 4-[2-(diethylamino)ethyl]-2,8,10-trimethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:41][C:42]1[CH:46]=[CH:45][O:44][N:43]=1)[CH2:20][O:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(SCC(N1C(C)=NN=N1)CO)CCCCCCCCCCCCCCC>CO.O1CCCC1>[CH2:1]([S:17][CH2:18][CH:19]([O:41][C:42]1[CH:46]=[CH:45][O:44][N:43]=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccon1
Agent: CCCCCCCCCCCCCCCCSCC(CO)n1nnnc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CO)Oc1ccon1
Yield: 93.5 %

Procedure:
A mixture of 7.30 g (11 mM) of 1-hexadecylthio-2-(3-isoxazolyloxy)-3-triphenylmethoxypropane 5j and 433 mg (2.3 mM) of p-toluenesulfonic acid monohydrate in 150 ml of methanol-tetrahydrofuran (1:1) mixture by the same procedure as described in (81) to give 4.25 g of the titled compound Vj1 (94% yield).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (34.2 mg, 0.059 mmol) and triethylamine (0.025 mL, 0.178 mmol) in DCM (0.5 mL) was added methoxyacetyl chloride (10.8 μL, 0.119 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (19.0 mg, 54.4%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.18 (d, J=6.6 Hz, 6H), 1.83-1.93 (m, 2H), 2.03-2.11 (m, 2H), 2.63 (t, J=5.8 Hz, 0.9H), 2.72 (t, J=5.3 Hz, 1.1H), 2.84-2.93 (m, 2H), 3.22-3.36 (m, 5H), 3.66 (t, J=5.8 Hz, 1.1H), 3.74 (t, J=6.1 Hz, 0.9H), 4.10-4.16 (m, 1H), 4.17 (br s, 0.9H), 4.19 (s, 1.1H), 4.49-4.56 (m, 1H), 5.65-5.72 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 476.5.
Reaction SMILES: [N:1]1([C:8]2[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:30]1[C:34](B(O)O)=[CH:33][C:32]2[CH:38]=[CH:39][CH:40]=[CH:41][C:31]1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1([C:8]2[C:9]([C:34]3[S:30][C:31]4[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=4[CH:33]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (2 mL) was added benzo[b]thiophen-2-ylboronic acid (180 mg, 1.00 mmol), K3PO4 (210 mg, 1.00 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) under nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in water (25 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 3-(azepan-1-yl)-2-(benzo[b]thiophen-2-yl)quinoxaline-6-carboxylate as a light yellow solid (82 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.[CH2:11]([CH:18]([C:24](=O)[CH3:25])[C:19](OCC)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:19]([OH:20])[C:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:24]([CH3:25])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl 2-benzyl-3-oxobutanoate(0.379 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature, and the reaction mixture was stirred for about 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[CH2:11](C([Sn])=C(CCCC)CCCC)[CH2:12]CC>CN(C=O)C.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH:11]=[CH2:12])=[CH:7][N:6]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)C)nc1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-isopropyl-pyridine (0.75 g, 3.7 mmol) was dissolved in DMF:THF (3:1, 6 mL). Tributylvinyltin (1.2 mL, 4.12 mmol) and Pd(PPh3)4 (0.070 g, 0.06 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 30 min. The reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C. The crude was purified through column chromatography (90% DCM-Hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-isopropyl-5-vinylpyridine as a light yellow liquid (0.5 g, 90% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:29][OH:30]>>[OH:30][CH2:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:23]1[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: OC[C@@H]1CCCCN1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCC[C@@H]1CO

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-piperidin-2ylmethanol (1.2 equiv) to give 162 (12.1 mg, M+1 411.1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[CH:26][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2cccc(Cl)c2)C1Cc1ccc(CC(F)(F)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of tert-butyl (4RS,5SR)-5-(3-chlorophenyl)-2-oxo-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidine-3-carboxylate (2.66 g, 5.12 mmol) in methanol-tetrahydrofuran (20 ml-20 ml) was added 1N sodium hydroxide (6.2 ml, 6.2 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give tert-butyl (1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethylcarbamate (2.11 g, 83%) as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:15]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][C:21]([OH:28])=[CH:20][C:19]=1[C:29]([F:32])([F:31])[F:30])([O-:17])=[O:16]>CC(C)=O>[CH2:7]([O:28][C:21]1[CH:20]=[C:19]([C:29]([F:32])([F:31])[F:30])[C:18]([N+:15]([O-:17])=[O:16])=[C:23]([C:24]([F:25])([F:26])[F:27])[CH:22]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1c(C(F)(F)F)cc(O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 13 h
Yield: 94.2 %

Procedure:
Under ice cooling, potassium carbonate (7.23 g, 52.3 mmol) and benzyl bromide (5.45 mL, 45.8 mmol) were added to a solution of 4-nitro-3,5-bis(trifluoromethyl)phenol (12.0 g, 43.6 mmol) in acetone (250 mL). After stirring at 50° C. for 13 hours, the reaction mixture was filtered and the insoluble matter was washed with acetone. To the residue obtained by distilling the filtrate under reduced pressure, ethyl acetate and water were added to allow it to separate into layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was recrystallized from hexane-acetone, whereby 15.0 g (yield: 94.3%) of 4-benzyloxy-2,6-bis(trifluoromethyl)nitrobenzene was obtained as pale yellow needle-like crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:10]([O:12][CH3:13])=[O:11])[C:7]([OH:9])=O.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[O:22][CH2:23]C.CC(O[CH2:31][CH2:32][C@H:33]([NH2:37])[C:34]([OH:36])=[O:35])=O>ClCCl>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:10]([O:12][CH3:13])=[O:11])[C:7]([NH:37][CH:33]([CH2:32][CH2:31][C:21]([O:22][CH3:23])=[O:25])[C:34]([OH:36])=[O:35])=[O:9]
Reactant: COC(=O)C(C(=O)O)=C1SC=CS1
Reactant: CC(=O)OCC[C@H](N)C(=O)O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(NC(=O)C(C(=O)OC)=C1SC=CS1)C(=O)O
Yield: 90.9 %

Procedure:
2-(1,3-Dithiol-2-ylidene)-3-methoxy-3-oxopropionic acid (3) (109 g) was suspended in dichloromethane (1 l), followed by the addition of 61 g of triethylamine under ice-cooled stirring. To the resulting mixture, ethyl chlorocarbonate (60 g) was added dropwise under ice-cooled stirring over 30 minutes. To a solution of 88.5 g of γ-methyl L-glutamate and 61 g of triethylamine in dichloromethane (1 l), the thus-obtained solution was added dropwise at 10° C. over 1.5 hours. After the resulting mixture was stirred at room temperature for 10 hours, the solvent was removed under reduced pressure. Ethyl acetate (2 l) was added to the residue, and the resultant precipitate was filtered off. After the filtrate was washed with 1 N hydrochloric acid and then with water, the solvent was removed under reduced pressure. The residue was dissolved in methanol (800 ml). Activated carbon (15 g) was added, followed by stirring at 40° C. for 1 hour. The activated carbon was filtered off, and the methanol was removed under reduced pressure. The residue was dissolved in toluene (500 ml) and the toluene was then removed under reduced pressure, whereby 2-((2-(1,3-dithiol-2-ylidene)-3-methoxy-3-oxopropanoyl)amino)-5-methoxy-5-oxopentanoic acid (4) (164 g, yield: 91%) was obtained as a brown oil.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([Br:36])=[CH:17][C:18]=1[N:19]([C@H:29]1[CH2:34][CH2:33][C@H:32](O)[CH2:31][CH2:30]1)[C:20]([C@H:22]1[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]1)=[O:21])=[O:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([Br:36])=[CH:17][C:18]=1[N:19]([C@H:29]1[CH2:34][CH2:33][C@@H:32]([F:7])[CH2:31][CH2:30]1)[C:20]([C@H:22]1[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]1)=[O:21])=[O:13].[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([Br:36])=[CH:17][C:18]=1[N:19]([C@H:29]1[CH2:34][CH2:33][C@H:32]([F:7])[CH2:31][CH2:30]1)[C:20]([C@H:22]1[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]1)=[O:21])=[O:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (diethylamino)sulfur trifluoride (0.24 mL, 1.82 mmol) in DCM (2.7 mL) pyridine (0.27 mL, 3.34 mmol) was added followed by dropwise addition of 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (150 mg, 0.32 mmol) in DCM (2.0 mL) during 10 min. The mixture was stirred for 16 h at room temperature. It was cooled in ice-bath and saturated NaHCO3 was added slowly to neutralize the excess reagent. The mixture was stirred at room temperature for 3 h. It was extracted with DCM (100 mL), washed with brine, dried (MgSO4) and evaporated. The crude was chromatographed over silica gel (hexane:EtOAc—95:5 and 90:10 as eluents) yielding pure 5-bromo-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (28 mg, 18%) and 5-bromo-3-[(trans-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (22 mg, 14%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>CN(C)C=O.O.CO>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1.5 g (6.2 mmol) of 7-benzylxanthine from stage b) were dissolved in 50 ml of dimethylformamide at 50° C. and treated in portions with 0.149 g (6.2 mmol) of sodium hydride and stirred at 50° C. for one hour. 0.67 ml (6.2 mmol) of isobutyl bromide was added dropwise and the mixture was heated to 80° C. After 5 hours, a further 0.2 ml (1.86 mmol) of isobutyl bromide was added and the mixture was stirred for a further 5 hours. 12 ml of water and 5 ml of methanol were then added, the mixture was stirred at room temperature for 2 hours, a further 60 ml of water were added and the mixture was extracted three times using methyl tert-butyl ether. The organic phases were washed with water, dried using magnesium sulfate and concentrated under reduced pressure and the residue was purified by flash chromatography on a silica gel column, dichloromethane/methanol (99/1).